Lithiated 1,3-dithiane, addition

Propenyl)-1,3-dithiane, after lithiation and addition of zinc chloride, reacts with ethyl 2-oxopropanoate to give preferentially the. vvn-adduct37, which is an intermediate in the synthesis of racemic /ra .s-tetrahydro-2,3-dimethyl-5-oxo-2-furancarboxylic acid. It is assumed, that the ethoxycarbonyl group is brought to a pseudoaxial position in the cyclic transition state by the chelating zinc cation. 

The addition of a lithiated dithiane to a chiral a,/J-unsaturated sulfone has been reported, however, the stereochemical outcome and the diastereoselectivity was not addressed20. The addition of (lithiomcthylsulfonyl)benzenc to a chiral y-alkoxy-a-trimethylsilyl-aj-unsaturated sulfone gave exclusively the, vr -adduct1 2 3 4 5 7 8 9 10 11 12. 

Ogura and coworkers178,179 continued their study of the addition of lithiated heterocycles to 2,3 5,6-di-0-isopropylidene-L-gulono-l,4-lactone (50) and related compounds. In the case of the addition of lithiated 1,3-dithiane to 50, it was shown178 by X-ray crystal-structure analysis that l-(l,3-dithian-2-yl)-2,3 5,6-di-0-isopropylidene-/3-L-gulofuranose is R at the anomeric carbon atom. This demonstrates that the product of this reaction is, surprisingly, the more sterically hindered of the two products possible. This is the opposite of that predicted for addition of the lithiated dithiane from the less hindered side of 50 if no equilibration of the initial adduct is involved. 

Sulfonyl carbanions react readily with oxiranes, usually on the less hindered site With 2,3-disubstituted oxiranes, harsher conditions have to be used ° the addition of HMPA and/or BF3 Et20 can enhance the rate and the yield of the reaction, as in the case of lithiated dithianes. The reaction has been widely employed in organic... 

The side chain at C-7 is introduced with high selectivity the aldehyde group, obtained by desilylation and Dess-Martin oxidation, reacts regioselectively with the lithiated dithiane 18, since attack at the keto group is sterically hindered. In addition, the CP skeleton shields one side of the aldehyde, so that the desired diastereomer 19 is obtained as major product in a ratio of 11 1. 

Smith et al. have developed a very elegant route to complex polyol structures by sequential dithiane-epoxide coupling reactions (Scheme 7) [16]. Following the work of Tietze [17], 2-silyl-1,3-dithianes 42 are deprotonated with /BuLi in ether and converted into the stable lithium alk-oxides 43 with enantiomerically pure epoxides. A fast 1,4-Brook rearrangement occurs only after the addition of 0.3 equivalents of hexamethyl-phosphoramide (HMPA) or 1,3-dimethylhexahy-dro-2-pyrimidone (DMPU) to the reaction mixture. A new lithiated dithiane 44 that can undergo... 

The intramolecular carbonyl addition of a lithiated dithiane to a ketme was used in the synthesis of ro-caglamide, an anticancer compound, in 64% yield. a-Hydroxy ketones having fungicidal activity were prepared from the reaction of lithiated 2-alkyldi-thianes with 3-pyridyl ketones. ... 

Diethoxyphosphinyi-2-buten-4-oli reacts with lithiated dithianes followed by an intermolecular Wittig-Homer reaction to produce fused y-lactones (equation 37). The reaction of 2-lithio-l,3-di-thianes with nitroarenes gives 2- or 4-[(l,3-dithian)-2 -yl]cyclohexa-3,5(or 2,5-)-diene-l-nitronate compounds (conjugate addition products), free nitroarene r cal anions (redox products), 1,3-dithianes and 2,2 -bis( 1,3-dithianes). ... 

Substituted 1,3-dithianes have been carboxylated with good yields. The usual procedure involves pouring the solution of the lithiated dithiane onto powdered dry ice, covered with Et20 (the addition may also be carried out by means of a syringe) [1,2]. With the unsubstituted dithiane the yields were moderate, due to occurrence of a very fast trans-metallation [2]. 

Next, the three building blocks were connected sequentially. Initial esterification was attempted via standard Mitsunobu conditions, which afforded poor results due to the formation of the undesired 2,4-phthahde. Nevertheless, esterification was achieved by the use of trifuryl phosphine and di/so-propyl azodicarboxylate, providing benzoic ester 545. The ensuing addition of previously lithiated dithiane 541 led to the open chain precursor 546. RCM under application of the Grubbs II catalyst 547 was successfully used to create the macrohde 548. Removal of the dithiane and cleavage of the methyl ethers as well as subsequent regioselective aromatic chlorination completed this total synthesis of radicicol (478) (Scheme 9.10). 

Regioselective opening of 2 ,3 -/yxo-epoxides with a lithiated dithian gave rise to branched structures of type (63, B=U or T) which could be converted (Scheme 9) into 3 -C-difluoromethyl compounds (64) and thence into analogues (65) with an additional fluorine atom at C-2 . 22 Alternatively, intermediates (63) could be used as precursors for 3 -C-hydroxymethyl systems (66), 23 and, by successive fluorination, fluoromethyl analogues of types (67) and (68) were obtained. 22 jn a synthesis of 3 -deoxy-3 -hydroxymethyl adenosine (69), the branched-chain sugar derivative (70),... 

Finally, Seebach has used the cyclic urea (69), DMPU, as a co-solvent in double lithiations, oxirane ring-opening, Wittig reactions, Michael additions of lithiated dithianes to cycloalkenones, and the selective generation of enolates." The interesting point here is that DMPU exhibits the same solvent effect as the carcinogen HMPA and might therefore be a safe substitute. 

In one case, the addition of lithiated 1,3-dithiane to ( )-l-nitropropene gave an adduct in modest enantiomeric excess (43% ee). In an independent study chiral lithium [(S)-(l-(dimethylamino)-ethyl](methyl)phenylcupratc and lithium mcthoxy(methyl)eupratc were reacted with ( )-(2-ni-troethenyl)benzene to give adducts in 1-2% enantiomeric excess36. 

The enantioselective lithiation of anisolechromium tricarbonyl was used by Schmalz and Schellhaas in a route towards the natural product (+)-ptilocaulin . In situ hthi-ation and silylation of 410 with ent-h M gave ewf-411 in an optimized 91% ee (reaction carried ont at — 100°C over 10 min, see Scheme 169). A second, substrate-directed lithiation with BuLi alone, formation of the copper derivative and a quench with crotyl bromide gave 420. The planar chirality and reactivity of the chromium complex was then exploited in a nucleophilic addition of dithiane, which generated ptilocaulin precnrsor 421 (Scheme 172). The stereochemistry of componnd 421 has also been used to direct dearomatizing additions, yielding other classes of enones. ... 

Thermolysis of 3-(ort o-anisoyl)-l-(l-piperidinyl)-3-cyclobutenes 807 in the presence of mesitylene affords angular-fused xanthones 809 via formation and ring closure of the intermediate 808 (Scheme 226) <1997TL3663>. Linear-fused xanthones 810 are prepared by nucleophilic addition of aryl and heteroaryl lithiates to dithiane protected benzopyrone-fused cyclobutenediones 811 followed by hydroysis of the dithiane protecting group (Scheme 227) <1996JA12473>. 

Lithiated 2-chloro- 1,3-dithiane- 1,3-dioxide undergoes an analogous addition reaction with aldehydes to give product mixtures displaying high diastereoselec-tivities (Scheme 21)77... 

Scheme 16.11 shows the completion of the total synthesis of azaspiracid-1, which followed with slight modifications, the synthesis of the originally proposed structure of azaspiracid-1 (la). This chemistry was also carried out with the corresponding ABCD enantiomer in similar yields. Thns, lithiation of dithiane 51 (n-BuLi n-BnjMg) followed by addition into pentafluorophenol ester 68 resulted in CJ-C27 ketone 69 (50% yield). Ketone 69 was then elaborated into diacetate 70, this time as the TBS ether at C-25, as this protecting group was easier to remove than the acetate used in the earlier work directed toward the original stractnre (see Scheme 16.8). Stille coupling of this allylic acetate (70) then proceeded smoothly, as before, affording the complete Cj-C q backbone 71, which was successfully elaborated to the correct structure of azaspiracid-1 (1), identical in all measured physical properties ( H NMR, C NMR, Rf, [aj ) to the natural material.

The chemistry outlined above was used in a synthesis of (-L)-ptilocaulin (Scheme 118). Lithiation of (75) followed by addition of copper chloride and an electrophile gave (76). Highly diastereoselective nucleophilic addition of 2-lithio-1,3-dithiane followed by treatment with TMS-chloride, oxidation, and hydrolysis produced the intermediate (77). 

Michael addition. ° The synthesis of the naturally occurring benz[a]anthraquinones, X-14881 (64 R = Me) and ochrotnycinone (R H) utilizes 2-phenyldithiane anion (Scheme 38), while 11-deoxydauno-mycinone was prepared using 2-methyldithiane. The formation of bicyclo[3.3.0]oct-l(5)-ene-2,6-dione utilizes 2-(2,2-diethoxyethyl)-l,3-dithiane anion. Conjugate addition of the highly stabilized anion (65) occurs readily with enamide (66), whereas the related acyclic anion (67) appears to be less reactive than the cyclic analog (Scheme 39). Conjugate addition of lithiated a-alkylthio monosulfoxide provides a new route for the synthesis of dihydrojasmone. ... 

Coupling of the two fragments 92 and 98 took place via lithiation of the vinyl stannane and conversion to the cuprate, followed by addition to epoxide 92 to give 99 in 89% yield. Conversion of 99 (R = MTM) to bis-silyl ether 100 was accomplished in 85% yield utilizing conventional methods. Homologation by a two-carbon unit was achieved by metalation of the dithiane group followed by the addition of dimethyloxalate to give the a-keto ester 101 in 96% yield. 

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